Catheter-based devices and associated methods for immune system neuromodulation

ABSTRACT

Catheter-based devices and associated methods for immune system neuromodulation of human patients are disclosed herein. One aspect of the present technology is directed to methods of treating a human patient diagnosed with an immune system condition. The methods can include intravascularly positioning a neuromodulation catheter within a blood vessel proximate to neural fibers innervating an immune system organ of the patient. The method also includes reducing sympathetic neural activity in the patient by delivering energy to the neural fibers innervating the immune system organ via the neuromodulation catheter. Reducing sympathetic neural activity improves a measurable physiological parameter corresponding to the immune system condition of the patient.

TECHNICAL FIELD

The present technology relates generally to modulation of nerves ofimmune system organs and associated systems and methods.

BACKGROUND

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS extend through tissue in almost every organ system of the humanbody. For example, some fibers extend from the brain, intertwine alongthe aorta, and branch out to various organs. As groups of fibersapproach specific organs, fibers particular to the organs can separatefrom the groups. Signals sent via these and other fibers can affectcharacteristics such as pupil diameter, gut motility, and urinaryoutput. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic activation of the SNS, however, is a common maladaptiveresponse that can drive the progression of many disease states.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1A is an anatomical view illustrating abdominal organs of a humanpatient, including a spleen, a splenic artery, and nearby organs andvessels.

FIG. 1B is a partially cross-sectional view illustrating neuromodulationat a treatment location within a splenic artery in accordance with anembodiment of the present technology.

FIG. 1C is a partially cross-sectional view illustrating neuromodulationat a treatment location within a splenic branch artery in accordancewith an embodiment of the present technology.

FIG. 2 is a partially schematic view illustrating a neuromodulationsystem configured in accordance with an embodiment of the presenttechnology.

FIG. 3 is a conceptual illustration of the SNS and how the braincommunicates with the body via the SNS.

DETAILED DESCRIPTION

The present technology is generally directed to modulation of nerves ofone or more immune system organs to treat immune system conditions,conditions associated with sympathetic activity (e.g., overactivity orhyperactivity) in immune system organs, and/or conditions associatedwith central sympathetic activity (e.g., overactivity or hyperactivity).For example, several embodiments are directed to modulation of nerves ofone or more immune system organs to treat autoimmune conditions andrelated conditions. As discussed in greater detail below, immune systemneuromodulation can include rendering neural fibers inert, inactive, orotherwise completely or partially reduced in function. This result canbe electrically-induced, thermally-induced, chemically-induced, orinduced by another mechanism during an immune system neuromodulationprocedure, e.g., a procedure including percutaneous transluminalintravascular access.

Specific details of several embodiments of the present technology aredescribed herein with reference to FIGS. 1A-3. The embodiments caninclude, for example, modulating nerves proximate (e.g., at or near) thesplenic artery, the splenic veins, the thymic artery, the thymic veins,another portion of a vessel or duct of an immune system organ, and/orother suitable structures. Although many of the embodiments aredescribed herein with respect to thermally-induced,electrically-induced, and chemically-induced approaches, other treatmentmodalities in addition to those described herein are within the scope ofthe present technology. Additionally, other embodiments of the presenttechnology can have different configurations, components, or proceduresthan those described herein. A person of ordinary skill in the art,therefore, will accordingly understand that the technology can haveother embodiments with additional elements and that the technology canhave other embodiments without several of the features shown anddescribed below with reference to FIGS. 1A-3.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to the treating clinician or clinician's controldevice. “Proximal” and “proximally” can refer to a position near or in adirection toward the clinician or clinician's control device. “Distal”or “distally” can refer to a position distant from or in a directionaway from the clinician or clinician's control device.

I. Immune System

The human immune system has two categories of defenses: innate andadaptive. The innate immune system response is non-specific, meaning itresponds to pathogens in a generic way and does not confer long-lastingimmunity against a pathogen. The innate system includes both humoral andchemical barriers and cellular barriers that utilize phagocytes(macrophages, neutrophils, and dendritic cells), mast cells,eosinophils, basophils, and natural killer cells. The adaptive immunesystem allows for stronger immune responses and immunological memory,meaning that a particular pathogen is remembered based on specificantigens. The adaptive immune system requires recognition ofnon-self-antigens during a process called antigen recognition. Theprimary cells of the adaptive immune system are lymphocytes, of which Bcells and T cells are the most common.

Organs involved in the immune system response include the spleen,thymus, lymph nodes, and bone marrow. The spleen is located in the leftupper quadrant of the abdomen, the thymus is located atop thepericardium within the chest cavity, and the lymph nodes and bone marroware distributed throughout the body. The sympathetic nervous systemappears to provide most of the efferent autonomic control over theimmune system organs, while most direct afferent input from the immunesystem appears to come from the bone marrow and lymph nodes.

II. Autoimmune Conditions

Autoimmune conditions are the result of an inappropriate immune responseagainst substances and tissues normally present in the body. Specializedcells located in the thymus and bone marrow normally present immaturelymphocytes with self-antigens and eliminate those that recognizeself-antigens. In subjects with autoimmune conditions, however, theimmune system is unable to tell the difference between healthy bodytissue and foreign antigens and, therefore, attacks the healthy bodytissue. This can result in a hypersensitivity reaction similar to theresponse in allergic conditions.

Autoimmune condition flares are often linked to psychological stressors,and the reaction to such stressors appears to have a neural component.For example, adaptational stress responses involve activation of boththe hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervoussystem (ANS), and both of these axes are thought to communicatebidirectionally with the immune system. Activation of the HPA axis andANS in response to an external stressor results in the release ofcortisol and catecholamines. These stress hormones generallydownregulate immune and inflammatory responses, but also influence thecentral nervous system.

The central sympathetic system regulates some aspects of the immunesystem, e.g., T-cell differentiation. Activation of the sympatheticnervous system primarily inhibits the activity of cells associated withthe innate immune system while either enhancing or inhibiting theactivity of cells associated with the acquired/adaptive immune system.The specific role of the sympathetic nerves depends on a variety offactors. For example, in a mouse model of systemic lupus erythematosus(SLE), alterations in sympathetic innervation have been linked todisease pathogenesis, which strongly supports the hypothesis that thesympathetic nervous system can modulate expression of autoimmunelymphoproliferative disease.

Current therapies for autoimmune conditions include anti-inflammatorydrugs such as steroids and immunosuppressive agents that locally orsystemically modify the immune system (e.g., TNFα antagonists and B celldepleting agents). However, these therapies generally require life-longadherence, and many patients still experience acute disease flares.

III. Immune System Neuromodulation

Immune system neuromodulation is the partial or complete incapacitationor other effective disruption or regulation of immune system nerves,e.g., nerves terminating in or originating from one or more immunesystem organs (including, but not limited to, the spleen, lymph nodes,bone marrow, thymus, and other suitable organs) or in structures closelyassociated with the immune system organs. In particular, immune systemneuromodulation comprises inhibiting, reducing, blocking, pacing,upregulating, and/or downregulating neural communication along neuralfibers (e.g., efferent and/or afferent neural fibers) innervating one ormore immune system organs. Such incapacitation, disruption, and/orregulation can be long-term (e.g., permanent or for periods of months,years, or decades) or short-term (e.g., for periods of minutes, hours,days, or weeks). While long-term disruption of the immune system nervescan be desirable for alleviating symptoms and other sequelae associatedwith autoimmune conditions and other immune system conditions overlonger periods of time, short-term modulation of the immune systemnerves may also be desirable, for example, to generate a temporaryreduction in symptoms or to address other issues.

As noted previously, there is significant sympathetic input to allcomponents of the immune system, and immune system autonomic neuralactivity (increased sympathetic drive or decreased parasympatheticdrive, or a change in the ratio thereof) can cause or exacerbate variousimmune system conditions, including for example autoimmune conditionssuch as multiple sclerosis, lupus, psoriasis, and other immune systemconditions. Immune system neuromodulation is expected to be useful intreating these conditions, for example by reducing mechanisms ofinflammation and modulating the immune response. For example, thedisclosed methods and systems for immune system neuromodulation areexpected to cause an improvement (e.g., a reduction) in one or moremarkers of inflammation, (e.g., interleukins, high-sensitivityC-reactive proteins, erythrocyte sedimentation rate (ESR), heat shockproteins, and/or other suitable markers) in patients diagnosed withautoimmune conditions and/or other patients. Similarly, the disclosedmethods and systems for immune system neuromodulation are expected toreduce the need for steroid or immune modulating agents (e.g., tumornecrosis factor inhibitors) in patients diagnosed with autoimmunediseases and/or other patients.

Furthermore, afferent sympathetic activity from immune system organs cancontribute to central sympathetic tone or drive. Accordingly, immunesystem neuromodulation is expected to be useful in treating clinicalconditions associated with central sympathetic activity (e.g.,overactivity or hyperactivity), particularly conditions associated withcentral sympathetic overstimulation. Conditions associated with centralsympathetic activity (e.g., overactivity or hyperactivity) include, forexample, hypertension, heart failure, acute myocardial infarction,metabolic syndrome, insulin resistance, diabetes, left ventricularhypertrophy, chronic and end stage renal disease, inappropriate fluidretention in heart failure, cardio-renal syndrome, polycystic kidneydisease, polycystic ovary syndrome, osteoporosis, erectile dysfunction,and sudden death, among other conditions.

In certain patients, reducing sympathetic drive in one or more immunesystem organs, reducing central sympathetic drive, and/or other benefitsfrom immune system neuromodulation are expected to outweigh the completeor partial loss of sympathetic-nerve functionality in treated immunesystem organs.

Several properties of the immune system organ vasculature may inform thedesign of treatment devices and associated methods for achieving immunesystem neuromodulation (e.g., via intravascular access), and imposespecific design requirements for such devices. Specific designrequirements may include accessing the immune system organ blood vessels(e.g., splenic artery, splenic vein, thymic artery, thymic vein),facilitating stable contact between the energy delivery elements of suchdevices and a luminal surface or wall of the immune system organ bloodvessel, and/or effectively modulating the immune system nerves with theneuromodulatory apparatus.

Potential targets for immune system neuromodulation include nervesinnervating immune system organs such as the spleen, thymus, and lymphnodes. Among the immune system organs, the spleen can be a particularlywell-suited target for neuromodulation. In addition to acting as a bloodfilter and blood reserve, the spleen plays an important role in theimmune system by synthesizing antibodies in its white pulp and removingantibody-coated bacteria and blood cells by way of blood and lymph nodecirculation. Further, the spleen contains in its blood reserves half ofthe body's monocytes, which turn into dendritic cells upon migrating toinjured tissue.

Splenic nerve activity can have a variety of effects on other organs andon the central sympathetic system. For example, the splenorenal reflexcan include increased sympathetic efferent communication to renal nervesin response to increased afferent communication from splenic nerves. Theincreased efferent communication to renal nerves can decrease renalblood flow and trigger the renin-angiotensin-aldosterone system,ultimately causing an increase in blood pressure. Splenic afferentactivity also can affect cardiopulmonary sympathetic nerve activity. Themechanism of the sympathetic responses to splenic nerve activity canoriginate, for example, in the spine or the brain. Increases in splenicafferent activity can occur, for example, when mechanoreceptors of thespleen sense increases in postcapillary venous pressure. Splenicefferent activity also can have systemic significance. For example, thespleen can regulate blood volume, e.g., by releasing blood to counteracthypovolemia and/or causing fluid to move from blood into lymph tocounteract hypervolemia. In addition to its role in treating autoimmuneconditions and other immune system conditions, splenic neuromodulationmay have anticoagulant effects. Therefore, splenic neuromodulation mayalso be used in situations where anticoagulant or antiplatelet effectsare desired.

A. Selected Examples of Neuromodulation Modalities

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the immune system organs.Immune system neuromodulation in accordance with embodiments of thepresent technology, for example, can be electrically-induced,thermally-induced, chemically-induced, or induced in another suitablemanner or combination of manners at one or more suitable treatmentlocations during a treatment procedure. For example, the purposefulapplication of radio frequency (RF) energy (monopolar and/or bipolar),pulsed RF energy, microwave energy, optical energy, ultrasound energy(e.g., intravascularly delivered ultrasound, extracorporeal ultrasound,high-intensity focused ultrasound (HIFU)), magnetic energy, direct heat,cryotherapeutic energy, chemicals (e.g., drugs or other agents), orcombinations thereof to tissue at a treatment location can induce one ormore desired effects at the treatment location, e.g., broadly across thetreatment location or at localized regions of the treatment location.

FIG. 1A is an anatomical view illustrating the abdominal organs,including the spleen 20, splenic artery 28, and splenic branch arteries21. Referring to FIG. 1A, treatment procedures in accordance withembodiments of the present technology can include applying a treatmentmodality at one or more treatment locations proximate a structure havinga relatively high concentration of immune system nerves. In someembodiments, for example, the treatment locations can be proximateportions of the splenic artery 28, an ostium of the splenic artery 28, asplenic branch artery 21, an ostium of a splenic branch artery 21, thesplenic vein, an ostium of the splenic vein, or a branch of the splenicvein, another portion of a vessel or duct of an immune system organ,and/or another suitable structure.

FIGS. 1B and 1C, for example, are cross-sectional views illustrating,respectively, neuromodulation at treatment locations within the splenicartery and a splenic branch artery. As shown in FIG. 1B, a treatmentdevice 31 including a shaft 32 and a therapeutic element 34 can beextended toward the splenic artery 38 to locate the therapeutic element34 at a treatment location within the splenic artery 38. Similarly, asshown in FIG. 1C, a treatment device 41 can be extended toward a splenicbranch artery 40 to locate the therapeutic element 44 at a treatmentlocation within the splenic branch artery 40. The therapeutic element 34or 44 can be configured for neuromodulation at the treatment locationsvia a suitable treatment modality, e.g., cryotherapeutic, direct heat,electrode-based, transducer-based, chemical-based, or another suitabletreatment modality.

The treatment location can be proximate (e.g., at or near) a vessel orduct wall (e.g., a wall of the splenic artery, the splenic vein, asplenic branch artery, another portion of a vessel or duct of an immunesystem organ, and/or another suitable structure), and the treated tissuecan include tissue proximate the treatment location. For example, withregard to the splenic artery 38, a treatment procedure can includemodulating nerves in the splenic plexus, which lay at least partiallywithin or adjacent to the adventitia of the splenic artery. In someembodiments it may be desirable to modulate immune system nerves from atreatment location within a vessel and in close proximity to an immunesystem organ, e.g., closer to the immune system organ than to a trunk ofthe vessel. This can increase the likelihood of modulating nervesspecific to the immune system organ, while decreasing the likelihood ofmodulating nerves that extend to other organs. Vessels can decrease indiameter and become more tortuous as they extend toward an immune systemorgan. Accordingly, modulating immune system nerves from a treatmentlocation in close proximity to an immune system organ can include usinga device (e.g., a treatment device 31 or 41) having size, flexibility,torque-ability, kink resistance, and/or other characteristics suitablefor accessing narrow and/or tortuous portions of vessels.

In some embodiments, the purposeful application of energy (e.g.,electrical energy, thermal energy, etc.) to tissue can induce one ormore desired thermal heating and/or cooling effects on localized regionsof the splenic artery, for example, and adjacent regions along all or aportion of the splenic plexus, which lay at least partially within oradjacent to the adventitia of the splenic artery. Some embodiments ofthe present technology, for example, include cryotherapeutic immunesystem neuromodulation (alone or in combination with another treatmentmodality), which can include cooling tissue at a treatment location in amanner that modulates neural function. For example, sufficiently coolingat least a portion of a sympathetic nerve can slow or potentially blockconduction of neural signals to produce a prolonged or permanentreduction in sympathetic activity. The mechanisms of cryotherapeutictissue damage include, for example, direct cell injury (e.g., necrosis),vascular or luminal injury (e.g., starving the cells of nutrients bydamaging supplying blood vessels), and sublethal hypothermia withsubsequent apoptosis. Exposure to cryotherapeutic cooling can causeacute cell death (e.g., immediately after exposure) and/or delayed celldeath (e.g., during tissue thawing and subsequent hyperperfusion).Several embodiments of the present technology include cooling astructure at or near an inner surface of a vessel or duct wall such thatproximate (e.g., adjacent) tissue is effectively cooled to a depth wheresympathetic nerves reside. For example, a cooling structure can becooled to the extent that it causes therapeutically effective cryogenicneuromodulation. Sufficiently cooling at least a portion of asympathetic immune system nerve may slow or potentially block conductionof neural signals to produce a prolonged or permanent reduction inimmune system sympathetic activity. In some embodiments, acryotherapeutic treatment modality can include cooling that is notconfigured to cause neuromodulation. For example, the cooling can be ator above cryogenic temperatures and can be used to controlneuromodulation via another treatment modality, e.g., to reduce damageto non-targeted tissue when targeted tissue adjacent to the non-targetedtissue is heated.

Cryotherapeutic treatment can be beneficial in certain embodiments. Forexample, rapidly cooling tissue can provide an analgesic effect suchthat cryotherapeutic treatment can be less painful than other treatmentmodalities. Neuromodulation using cryotherapeutic treatment cantherefore require less analgesic medication to maintain patient comfortduring a treatment procedure compared to neuromodulation using othertreatment modalities. Additionally, reducing pain can reduce patientmovement and thereby increase operator success and/or reduce proceduralcomplications. Cryogenic cooling also typically does not causesignificant collagen tightening, and therefore is not typicallyassociated with vessel or duct stenosis. In some embodiments,cryotherapeutic treatment can include cooling at temperatures that cancause therapeutic elements to adhere to moist tissue. This can bebeneficial because it can promote stable, consistent, and continuedcontact during treatment. The typical conditions of treatment can makethis an attractive feature because, for example, patients can moveduring treatment, catheters associated with therapeutic elements canmove, and/or respiration can cause the spleen and other immune systemorgans to rise and fall and thereby move their associated vessels andducts. In addition, blood flow is pulsatile and can cause structures topulse. Cryogenic adhesion also can facilitate intravascular andintraluminal positioning, particularly in relatively small structures(e.g., relatively short arteries) in which stable positioning can bedifficult to achieve.

As an alternative to or in conjunction with cryotherapeutic cooling,other suitable energy delivery techniques, such as electrode-based ortransducer-based approaches, can be used for therapeutically-effectiveimmune system neuromodulation. Electrode-based or transducer-basedtreatment, for example, can include delivering electrical energy and/oranother form of energy to tissue and/or heating tissue at a treatmentlocation in a manner that modulates neural function. For example,sufficiently stimulating and/or heating at least a portion of asympathetic immune system nerve can slow or potentially block conductionof neural signals to produce a prolonged or permanent reduction insympathetic activity. As noted previously, suitable energy modalitiesinclude, for example, RF energy (monopolar and/or bipolar), pulsed RFenergy, microwave energy, ultrasound energy (e.g., intravascularlydelivered ultrasound, extracorporeal ultrasound, HIFU), laser energy,optical energy, magnetic energy, direct heat, or other suitable energymodalities alone or in combination. Where a system uses a monopolarconfiguration, a return electrode or ground patch fixed externally onthe subject can be used. Moreover, electrodes (or other energy deliveryelements) can be used alone or with other electrodes in amulti-electrode array. Examples of suitable multi-electrode devices aredescribed in U.S. patent application Ser. No. 13/281,360, filed October25, 2011, and incorporated herein by reference in its entirety. Othersuitable devices and technologies, such as cryotherapeutic devices, aredescribed in U.S. patent application Ser. No. 13/279,330, filed Oct. 23,2011, and additional thermal devices are described in U.S. patentapplication Ser. No. 13/279,205, filed Oct. 21, 2011, each of which areincorporated herein by reference in their entireties.

Thermal effects can include both thermal ablation and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating) to partially or completely disrupt the ability of anerve to transmit a signal. Desired thermal heating effects may include,for example, raising the temperature of target neural fibers to a targettemperature to achieve non-ablative thermal alteration, or to or above ahigher target temperature to achieve ablative thermal alteration. Forexample, a target temperature for non-ablative thermal alteration may begreater than body temperature (e.g., about 37° C.) but less than about45° C., while a target temperature for ablative thermal alteration maybe greater than about 45° C. Exposure to thermal energy between aboutbody temperature and about 45° C. may induce non-ablative thermalalteration via moderate heating of target neural fibers or of vascularor luminal structures that perfuse the target neural fibers. In caseswhere vascular or luminal structures are affected, the target neuralfibers may be denied perfusion, resulting in necrosis of the neuraltissue. For example, this may induce non-ablative thermal alteration inthe fibers or structures. Exposure to thermal energy greater than about45° C. (e.g., greater than about 60° C.) may induce thermal ablation viasubstantial heating of target neural fibers or of vascular or luminalstructures that perfuse the target fibers. In some patients, it may bedesirable to achieve temperatures that thermally ablate the targetneural fibers or the vascular or luminal structures, but that are lessthan about 90° C., e.g., less than about 85° C., less than about 80° C.,or less than about 75° C. Other embodiments can include heating tissueto a variety of other suitable temperatures.

In some embodiments, immune system neuromodulation can include achemical-based treatment modality alone or in combination with anothertreatment modality. Neuromodulation using chemical-based treatment caninclude delivering one or more chemicals (e.g., drugs or other agents)to tissue at a treatment location in a manner that modulates neuralfunction. The chemical, for example, can be selected to affect thetreatment location generally or to selectively affect some structures atthe treatment location over other structures. For example, thechemical(s) can be guanethidine, ethanol, phenol, vincristine, aneurotoxin, or another suitable agent selected to alter, damage, ordisrupt nerves. In some embodiments, energy (e.g., light, ultrasound, oranother suitable type of energy) can be used to activate the chemical(s)and/or to cause the chemical(s) to become more bioavailable. A varietyof suitable techniques can be used to deliver chemicals to tissue at atreatment location. For example, chemicals can be delivered via one ormore devices, such as needles originating outside the body or within thevasculature or delivery pumps (see, e.g., U.S. Pat. No. 6,978,174, thedisclosure of which is hereby incorporated by reference in itsentirety). In an intravascular example, a catheter can be used tointravascularly position a therapeutic element including a plurality ofneedles (e.g., micro-needles) that can be retracted or otherwise blockedprior to deployment. In other embodiments, a chemical can be introducedinto tissue at a treatment location via simple diffusion through avessel or duct wall, electrophoresis, or another suitable mechanism.Similar techniques can be used to introduce chemicals that are notconfigured to cause neuromodulation, but rather to facilitateneuromodulation via another treatment modality. Examples of suchchemicals include, but are not limited to, anesthetic agents andcontrast agents.

In some embodiments, a treatment procedure can include applying asuitable treatment modality at a treatment location in a testing stepfollowed by a treatment step. The testing step, for example, can includeapplying the treatment modality at a lower intensity and/or for ashorter duration than during the treatment step. This can allow anoperator to determine (e.g., by neural activity sensors and/or patientfeedback) whether nerves proximate to the treatment location aresuitable for modulation. Performing a testing step can be particularlyuseful for treatment procedures in which targeted nerves are closelyassociated with nerves that could cause undesirable side effects ifmodulated during a subsequent treatment step.

IV. Methods for Treatment of Immune System Conditions

Sympathetic neural activity in immune system organs can cause orexacerbate immune system conditions, e.g., autoimmune conditions such asmultiple sclerosis, lupus, psoriasis, and other immune systemconditions. As noted previously, disclosed herein are severalembodiments of methods directed to treatment of autoimmune conditionsand other immune system conditions, as well as conditions associatedwith sympathetic activity (e.g., overactivity or hyperactivity) in theimmune system organs and/or conditions associated with centralsympathetic activity (e.g., overactivity or hyperactivity), using immunesystem neuromodulation. The methods disclosed herein may provide variousadvantages over a number of conventional approaches and techniques inthat they allow for the potential targeting of elevated sympatheticdrive, which may either be a cause of autoimmune conditions and otherimmune system conditions or a key mediator of the multiplemanifestations of these conditions. Also, the disclosed methods providefor localized treatment and limited duration treatment regimens, therebyreducing patient long-term compliance issues.

In certain embodiments, the methods provided herein comprise performingimmune system neuromodulation, thereby decreasing sympathetic immunesystem nerve activity. Immune system neuromodulation may be repeated oneor more times at various intervals until a desired sympathetic nerveactivity level or another therapeutic benchmark (e.g., target antibodytiter, target white blood cell (WBC) count, etc.) is reached. In oneembodiment, for example, a decrease in sympathetic nerve activity may beobserved via a marker of sympathetic nerve activity such as plasmanorepinephrine (noradrenaline) in autoimmune patients. Other measures ormarkers of sympathetic nerve activity can include muscle sympatheticnerve activity (MSNA), norepinephrine spillover, and/or heart ratevariability.

In certain embodiments of the methods provided herein, immune systemneuromodulation is expected to result in a decrease in sympathetic nerveactivity over a specific timeframe. For example, in certain of theseembodiments, sympathetic nerve activity levels are decreased over anextended timeframe, e.g., within about 1 month, 2 months, 3 months, 6months, 9 months or 12 months post-neuromodulation.

In several embodiments, the methods disclosed herein may comprise anadditional step of measuring sympathetic nerve activity levels, and incertain of these embodiments, the methods can further comprise comparingthe activity level to a baseline activity level. Such comparisons can beused to monitor therapeutic efficacy and to determine when and if torepeat the neuromodulation procedure. In certain embodiments, a baselinenerve activity level is derived from the subject undergoing treatment.For example, baseline nerve activity level may be measured in thesubject at one or more timepoints prior to treatment. A baseline nerveactivity value may represent sympathetic nerve activity at a specifictimepoint before neuromodulation, or it may represent an averageactivity level at two or more timepoints prior to neuromodulation. Incertain embodiments, the baseline value is based on nerve activityimmediately prior to treatment (e.g., after the subject has already beencatheterized). Alternatively, a baseline value may be derived from astandard value for nerve activity observed across the population as awhole or across a particular subpopulation. In certain embodiments,post-neuromodulation nerve activity levels are measured in extendedtimeframes post-neuromodulation, e.g., 3 months, 6 months or 12 monthspost-neuromodulation.

In certain embodiments of the methods provided herein, the methods aredesigned to decrease sympathetic nerve activity to a target level. Inthese embodiments, the methods include a step of measuring nerveactivity levels post-neuromodulation (e.g., 6 months posttreatment, 12months post-treatment, etc.) and comparing the resultant activity levelto a baseline activity level as discussed above. In certain of theseembodiments, the treatment is repeated until the target nerve activitylevel is reached. In other embodiments, the methods are simply designedto decrease nerve activity below a baseline level without requiring aparticular target activity level.

Immune system neuromodulation may be performed on a patient diagnosedwith an immune system condition such as an autoimmune condition toreduce or prevent an increase in one or more measurable physiologicalparameters corresponding to the condition. In some embodiments, forexample, immune system neuromodulation may prevent an increase in,maintain, or reduce the occurrence or severity of fatigue, fever, jointpain, stiffness, or swelling, skin lesions, blood markers ofinflammation (e.g., ESR, hsCRP, IL-1, IL-6), new demyelinated lesions inthe central nervous system (CNS), shortness of breath, chest pain,headaches, confusion, clumsiness, tingling, or weakness in patientsdiagnosed with an autoimmune condition. A reduction in a physiologicalparameter associated with an immune system condition may be determinedby qualitative or quantitative analysis before and after (e.g., 1, 3, 6,or 12 months after) an immune system neuromodulation procedure.

As discussed previously, the progression of autoimmune conditions andother immune system conditions may be related to sympatheticoveractivity and, correspondingly, the degree of sympathoexcitation in apatient may be related to the severity of the clinical presentation ofthe autoimmune condition and other immune system conditions. The nervesof the immune system may be positioned to be both a cause (via afferentnerve fibers) and a target (via efferent sympathetic nerves) of elevatedcentral sympathetic drive. In some embodiments, immune systemneuromodulation can be used to reduce central sympathetic drive in apatient diagnosed with an immune condition in a manner that treats thepatient for the immune condition. In some embodiments, for example, MSNAcan be reduced by at least about 10% in the patient within about threemonths after at least partially inhibiting sympathetic neural activityin nerves proximate an artery innervating an immune system organ.Similarly, in some instances immune system norepinephrine spillover toplasma can be reduced at least about 20% in the patient within aboutthree months after at least partially inhibiting sympathetic neuralactivity in nerves proximate an artery innervating an immune systemorgan. Additionally, measured immune system norepinephrine content(e.g., assessed in real-time via intravascular blood collectiontechniques) can be reduced (e.g., by at least about 5%, 10%, or by atleast 20%) in the patient within about three months after at leastpartially inhibiting sympathetic neural activity in nerves proximate anartery innervating an immune system organ.

In one prophetic example, a patient diagnosed with an autoimmunecondition can be subjected to a baseline assessment indicating a firstset of measurable parameters corresponding to the autoimmune condition.Such parameters can include, for example, antibody titers, WBC counts,blood markers of inflammation (e.g., ESR, hsCRP, IL-1, IL-6), imaging ofthe CNS for areas of demyelination, fatigue, fever, joint pain,stiffness, or swelling, skin lesions, shortness of breath, chest pain,headaches, confusion, clumsiness, tingling, or weakness. Followingbaseline assessment, the patient is subjected to an immune systemneuromodulation procedure. Such a procedure can, for example, includeany of the treatment modalities described herein or another treatmentmodality in accordance with the present technology. The treatment can beperformed on nerves proximate the splenic artery, the splenic vein,and/or another portion of a vessel or duct of an immune system organ.Following the treatment (e.g., 1, 3, 6, or 12 months after treatment),the patient can be subjected to a follow-up assessment. The follow-upassessment can indicate a measurable improvement in one or morephysiological parameters corresponding to the autoimmune condition.Additionally, one could measure the dose of immunosuppressant and immunemodulating drugs required for maintenance therapy both before and afteran immune system neuromodulation procedure, with a reduction inmedications being deemed as a marker of successful therapy.

The methods described herein address the sympathetic excess that isthought to be an underlying cause of autoimmune conditions and otherimmune system conditions or a central mechanism through which theseimmune system conditions manifest their multiple deleterious effects onpatients. In contrast, known therapies currently prescribed forautoimmune conditions and other immune system conditions typicallyaddress only specific manifestations of these conditions. Additionally,these known therapies can have significant limitations including limitedefficacy, and frequently require the patient to remain compliant withthe treatment regimen over time. In contrast, immune systemneuromodulation can be a one-time treatment that would be expected tohave durable benefits to inhibit the long-term disease progression andthereby achieve a favorable patient outcome. Unlike pharmacologictreatments that affect the entire body, it could also be a more targetedtherapy, preferentially affecting the immune system organs.

In some embodiments, patients diagnosed with an immune system conditioncan be treated with immune system neuromodulation alone. However, inother embodiments patients diagnosed with autoimmune conditions andother immune system conditions can be treated with combinations oftherapies for treating both primary causative modes of these conditionsas well as sequelae of these conditions. For example, combinations oftherapies can be tailored based on specific manifestations of thedisease in a particular patient.

Treatment of an immune system condition may refer to preventing thecondition, slowing the onset or rate of development of the condition,reducing the risk of developing the condition, preventing or delayingthe development of symptoms associated with the condition, reducing orending symptoms associated with the condition, generating a complete orpartial regression of the condition, or some combination thereof.

V. Selected Examples of Immune System Neuromodulation Systems andDevices

FIG. 2 is a partially schematic diagram illustrating an immune systemneuromodulation system 100 (“system 100”) configured in accordance withan embodiment of the present technology. The system 100 can include atreatment device 102, an energy source or console 104 (e.g., an RFenergy generator, a cryotherapy console, etc.), and a cable 106extending between the treatment device 102 and the console 104. Thetreatment device 102 can include a handle 108, a neuromodulationassembly 110, and an elongated shaft 112 extending between the handle108 and the neuromodulation assembly 110. The shaft 112 can beconfigured to locate the neuromodulation assembly 110 intravascularly orintraluminally at a treatment location (e.g., in or near the splenicartery, the splenic vein, another portion of a vessel or duct of animmune system organ, and/or another suitable structure), and theneuromodulation assembly 110 can be configured to provide or supporttherapeutically-effective neuromodulation at the treatment location. Insome embodiments, the shaft 112 and the neuromodulation assembly 110 canbe 3, 4, 5, 6, or 7 French or another suitable size. Furthermore, theshaft 112 and the neuromodulation assembly 110 can be partially or fullyradiopaque and/or can include radiopaque markers corresponding tomeasurements, e.g., every 5 cm.

Intravascular delivery can include percutaneously inserting a guide wire(not shown) within the vasculature and moving the shaft 112 and theneuromodulation assembly 110 along the guide wire until theneuromodulation assembly 110 reaches the treatment location. Forexample, the shaft 112 and the neuromodulation assembly 110 can includea guide-wire lumen (not shown) configured to receive the guide wire inan over-the-wire (OTW) or rapid-exchange configuration (RX). Other bodylumens (e.g., ducts or internal chambers) can be treated, for example,by non-percutaneously passing the shaft 112 and neuromodulation assembly110 through externally accessible passages of the body or other suitablemethods. In some embodiments, a distal end of the neuromodulationassembly 110 can terminate in an atraumatic rounded tip or cap (notshown). The treatment device 102 can also be a steerable ornon-isteerable catheter device configured for use without a guide wire.

The neuromodulation assembly 110 can have a single state orconfiguration, or it can be convertible between a plurality of states orconfigurations. For example, the neuromodulation assembly 110 can beconfigured to be delivered to the treatment location in a delivery stateand to provide or support therapeutically-effective neuromodulation in adeployed state. In these and other embodiments, the neuromodulationassembly 110 can have different sizes and/or shapes in the delivery anddeployed states. For example, the neuromodulation assembly 110 can havea low-profile configuration in the delivery state and an expandedconfiguration in the deployed state. In another example, theneuromodulation assembly 110 can be configured to deflect into contactwith a vessel wall in a delivery state. The neuromodulation assembly 110can be converted (e.g., placed or transformed) between the delivery anddeployed states via remote actuation, e.g., using an actuator 114 of thehandle 108. The actuator 114 can include a knob, a pin, a lever, abutton, a dial, or another suitable control component. In otherembodiments, the neuromodulation assembly 110 can be transformed betweenthe delivery and deployed states using other suitable mechanisms ortechniques.

In some embodiments, the neuromodulation assembly 110 can include anelongated member (not shown) that can be configured to curve (e.g.,arch) in the deployed state, e.g., in response to movement of theactuator 114. For example, the elongated member can be at leastpartially helical in the deployed state. In other embodiments, theneuromodulation assembly 110 can include a balloon (not shown) that canbe configured to be at least partially inflated in the deployed state.An elongated member, for example, can be well suited for carrying one ormore heating elements, electrodes, or transducers and for deliveringdirect heat, electrode-based, or transducer-based treatment. A balloon,for example, can be well suited for containing refrigerant (e.g., duringor shortly after liquid-to-gas phase change) and for deliveringcryotherapeutic treatment. In some embodiments, the neuromodulationassembly 110 can be configured for intravascular, transvascular,intraluminal, and/or transluminal delivery of chemicals. For example,the neuromodulation assembly 110 can include one or more openings (notshown), and chemicals (e.g., drugs or other agents) can be deliverablethrough the openings. For transvascular and transluminal delivery, theneuromodulation assembly 110 can include one or more needles (not shown)(e.g., retractable needles) and the openings can be at end portions ofthe needles.

The console 104 is configured to control, monitor, supply, or otherwisesupport operation of the treatment device 102. In other embodiments, thetreatment device 102 can be self-contained and/or otherwise configuredfor operation without connection to the console 104. As shown in FIG. 1,the console 104 can include a primary housing 116 having a display 118.The system 100 can include a control device 120 along the cable 106configured to initiate, terminate, and/or adjust operation of thetreatment device 102 directly and/or via the console 104. In otherembodiments, the system 100 can include another suitable controlmechanism. For example, the control device 120 can be incorporated intothe handle 108. The console 104 can be configured to execute anautomated control algorithm 122 and/or to receive control instructionsfrom an operator. Furthermore, the console 104 can be configured toprovide feedback to an operator before, during, and/or after a treatmentprocedure via the display 118 and/or an evaluation/feedback algorithm124. In some embodiments, the console 104 can include a processingdevice (not shown) having processing circuitry, e.g., a microprocessor.The processing device can be configured to execute stored instructionsrelating to the control algorithm 122 and/or the evaluation/feedbackalgorithm 124. Furthermore, the console 104 can be configured tocommunicate with the treatment device 102, e.g., via the cable 106. Forexample, the neuromodulation assembly 110 of the treatment device 102can include a sensor (not shown) (e.g., a recording electrode, atemperature sensor, a pressure sensor, or a flow rate sensor) and asensor lead (not shown) (e.g., an electrical lead or a pressure lead)configured to carry a signal from the sensor to the handle 108. Thecable 106 can be configured to carry the signal from the handle 108 tothe console 104.

The console 104 can have different configurations depending on thetreatment modality of the treatment device 102. For example, when thetreatment device 102 is configured for electrode-based ortransducer-based treatment, the console 104 can include an energygenerator (not shown) configured to generate RF energy, pulsed RFenergy, microwave energy, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, HIFU),magnetic energy, direct heat energy, or another suitable type of energy.In some embodiments, the console 104 can include an RF generatoroperably coupled to one or more electrodes (not shown) of theneuromodulation assembly 110. When the treatment device 102 isconfigured for cryotherapeutic treatment, the console 104 can include arefrigerant reservoir (not shown) and can be configured to supply thetreatment device 102 with refrigerant, e.g., pressurized refrigerant inliquid or substantially liquid phase. Similarly, when the treatmentdevice 102 is configured for chemical-based treatment, the console 104can include a chemical reservoir (not shown) and can be configured tosupply the treatment device 102 with one or more chemicals. In someembodiments, the treatment device 102 can include an adapter (not shown)(e.g., a luer lock) configured to be operably coupled to a syringe (notshown). The adapter can be fluidly connected to a lumen (not shown) ofthe treatment device 102, and the syringe can be used, for example, tomanually deliver one or more chemicals to the treatment location, towithdraw material from the treatment location, to inflate a balloon (notshown) of the neuromodulation assembly 110, to deflate a balloon of theneuromodulation assembly 110, or for another suitable purpose. In otherembodiments, the console 104 can have other suitable configurations.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative energy anda hypothermic source, making it capable of, for example, performing bothRF neuromodulation and cryo-neuromodulation. The distal end of thetreatment device may be straight (for example, a focal catheter),expandable (for example, an expanding mesh or cryoballoon), or have anyother configuration. For example, the distal end of the treatment devicecan be at least partially helical/spiral in the deployed state.Additionally or alternatively, the treatment device may be configured tocarry out one or more non-ablative neuromodulatory techniques. Forexample, the device may comprise a means for diffusing a drug orpharmaceutical compound at the target treatment area (e.g., a distalspray nozzle).

VI. Selected Examples of Treatment Procedures for Immune SystemNeuromodulation

Referring back to FIGS. 1B and 2B, in some embodiments the shaft 32 or42 and the therapeutic element 34 or 44 can be portions of a treatmentdevice at least partially corresponding to the treatment device 102shown in FIG. 2. The therapeutic element 34 or 44, for example, can beconfigured to radially expand into a deployed state at the treatmentlocation. In the deployed state, the therapeutic element 34 or 44 can beconfigured to contact an inner wall of a vessel and to form a suitablelesion or pattern of lesions without the need for repositioning. Forexample, the therapeutic element 34 or 44 can be configured to form asingle lesion or a series of lesions, e.g., overlapping ornon-overlapping. In some embodiments, the lesion or pattern of lesionscan extend around generally the entire circumference of the vessel, butcan still be non-circumferential at longitudinal segments or zones alonga lengthwise portion of the vessel. This can facilitate precise andefficient treatment with a low possibility of vessel stenosis. In otherembodiments, the therapeutic element 34 or 44 can be configured cause apartially-circumferential lesion or a fully-circumferential lesion at asingle longitudinal segment or zone of the vessel. During treatment, thetherapeutic element 34 or 44 can be configured for partial or fullocclusion of a vessel. Partial occlusion can be useful, for example, toreduce ischemia, while full occlusion can be useful, for example, toreduce interference (e.g., warming or cooling) caused by blood flowthrough the treatment location. In some embodiments, the therapeuticelement 34 or 44 can be configured to form therapeutically-effectiveneuromodulation (e.g., using ultrasound energy) without contacting avessel wall.

A variety of other suitable treatment locations are also possible in andaround the splenic artery 38 and 48, splenic branch arteries 30 and 40,splenic vein, other portions of vessels or ducts of immune systemorgans, and/or other suitable structures. For example, in some cases, itcan be more convenient to treat the splenic artery 38 or 48 at itstrunk, where it meets the celiac artery. It may also be possible toachieve the desired denervation by targeting the celiac artery, but insuch a case one would need to demonstrate that modulating the nerves didnot cause significant adverse consequences in other structures receivinginnervation from nerves proximate to the celiac trunk.

Furthermore, a treatment procedure can include treatment at any suitablenumber of treatment locations, e.g., a single treatment location, twotreatment locations, or more than two treatment locations. In someembodiments, different treatment locations can correspond to differentportions of the splenic artery 38 or 48, the splenic branch arteries 30or 40, the splenic vein, other portions of vessels and ducts of immunesystem organs, and/or other suitable structures proximate tissue havingrelatively high concentrations of immune system nerves. The shaft 32 or42 can be steerable (e.g., via one or more pull wires, a steerable guideor sheath catheter, etc.) and can be configured to move the therapeuticelement 34 or 44 between treatment locations. At each treatmentlocation, the therapeutic element 34 or 44 can be activated to causemodulation of nerves proximate the treatment location. Activating thetherapeutic element 34 or 44 can include, for example, heating, cooling,stimulating, or applying another suitable treatment modality at thetreatment location. Activating the therapeutic element 34 or 44 canfurther include applying various energy modalities at varying powerlevels or intensities or for various durations for achieving modulationof nerves proximate the treatment location. In some embodiments, powerlevels, intensities, and/or treatment duration can be determined andemployed using various algorithms for ensuring modulation of nerves atselect distances (e.g., depths) away from the treatment location.Furthermore, as noted previously, in some embodiments, the therapeuticelement 34 or 44 can be configured to introduce (e.g., inject) achemical (e.g., a drug or another agent) into target tissue at thetreatment location. Such chemicals or agents can be applied at variousconcentrations depending on treatment location and the relative depth ofthe target nerves.

The splenic artery branches off the celiac artery, which in turnbranches from the abdominal aorta, so the least invasive access routefor the therapeutic element 34 or 44 to be positioned at a treatmentlocation within the splenic artery would typically be through femoral,brachial, or radial access to the abdominal aorta. However, othersuitable catheterization paths may be used. Catheterization can beguided, for example, using imaging, e.g., magnetic resonance, computedtomography, fluoroscopy, ultrasound, intravascular ultrasound, opticalcoherence tomography, or another suitable imaging modality. Thetherapeutic element 34 or 44 can be configured to accommodate theanatomy of the splenic artery 38 or 48, splenic branch artery 30 or 40,the splenic vein, another portion of a vessel or duct of an immunesystem organ, and/or another suitable structure. For example, thetherapeutic element 34 or 44 can include a balloon (not shown)configured to inflate to a size generally corresponding to the internalsize of the splenic artery 38 or 48, splenic branch artery 30 or 40,splenic vein, another portion of a vessel or duct of an immune systemorgan, and/or another suitable structure. In some embodiments, thetherapeutic element 34 or 44 can be an implantable device and atreatment procedure can include locating the therapeutic element 34 or44 at the treatment location using the shaft 32 or 42, fixing thetherapeutic element 34 or 44 at the treatment location, separating thetherapeutic element 34 or 44 from the shaft 32 or 42, and withdrawingthe shaft 32 or 42. Other treatment procedures for modulation of immunesystem nerves in accordance with embodiments of the present technologyare also possible.

As mentioned previously, the methods disclosed herein may use a varietyof suitable energy modalities, including RF energy, pulsed RF energy,microwave energy, laser energy, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, HIFU),magnetic energy, direct heat, cryotherapy, or a combination thereof.Alternatively or in addition to these techniques, the methods mayutilize one or more non-ablative neuromodulatory techniques. Forexample, the methods may utilize non-ablative SNS denervation by removalof target nerves, injection of target nerves with a destructive drug orpharmaceutical compound, or treatment of the target nerves withnon-ablative energy modalities. In certain embodiments, the amount ofreduction of the sympathetic nerve activity may vary depending on thespecific technique being used.

In one example, the treatment device 102 set forth in FIG. 2 can be anRF energy emitting device and RF energy can be delivered through energydelivery elements or electrodes to one or more locations along the innerwall of a first immune system blood vessel (e.g., a splenic artery orvein) for predetermined periods of time (e.g., 120 seconds). Anobjective of a treatment may be, for example, to heat tissue to adesired depth (e.g., at least about 3 mm) to a temperature (e.g., about65° C.) that would modulate one or more nerve fibers associated with oradjacent to one or more lesions formed in the vessel wall. A clinicalobjective of the procedure typically is to neuromodulate a sufficientnumber of immune system nerves (efferent and/or afferent nerves) tocause a reduction in sympathetic tone or drive to one or more immunesystem organs without, for example, disrupting immune system functionand while minimizing vessel trauma. If the objective of a treatment ismet (e.g., tissue is heated to about 65° C. to a depth of about 3 mm)the probability of modulating immune system nerve tissue (e.g., alteringnerve function) is high. In some embodiments, a single neuromodulationtreatment procedure can provide for sufficient modulation of targetsympathetic nerves (e.g., modulation of a sufficient number of nervefibers) to provide a desired clinical outcome. In other embodiments,more than one treatment may be beneficial for modulating a desirednumber or volume of target nerve fibers, and thereby achieving clinicalsuccess. In other embodiments, an objective may include reducing oreliminating immune system nerve function completely.

In a specific example of using RF energy for immune system nervemodulation, a clinician can commence treatment, which causes the controlalgorithm 122 (FIG. 2) to initiate instructions to the generator (notshown) to gradually adjust its power output to a first power level(e.g., 5 watts) over a first time period (e.g., 15 seconds). The powerincrease during the first time period is generally linear. As a result,the generator increases its power output at a generally constant rate ofpower/time, i.e., in a linear manner. Alternatively, the power increasemay be non-linear (e.g., exponential or parabolic) with a variable rateof increase. Once the first power level and the first time are achieved,the algorithm may hold at the first power level until a secondpredetermined period of time has elapsed (e.g., 3 seconds). At theconclusion of the second period of time, power is again increased by apredetermined increment (e.g., 1 watt) to a second power level over athird predetermined period of time (e.g., 1 second). This power ramp inpredetermined increments of about 1 watt over predetermined periods oftime may continue until a maximum power P_(MAX) is achieved or someother condition is satisfied. In one embodiment, P_(MAX) is 8 watts. Inanother embodiment P_(MAX) is 10 watts, or in a further embodiment,P_(MAX) is 6.5 watts. In some embodiments, P_(MAX) can be about 6 wattsto about 10 watts. Optionally, the power may be maintained at themaximum power P_(MAX) for a desired period of time or up to the desiredtotal treatment time (e.g., up to about 120 seconds), or until aspecified temperature is reached or maintained for a specified timeperiod.

In another specific example, the treatment device 102 in FIG. 2 can be acryogenic device and cryogenic cooling can be applied for one or morecycles (e.g., for 30 second increments, 60 second increments, 90 secondincrements, etc.) in one or more locations along the circumferenceand/or length of the first immune system blood vessel. The coolingcycles can be, for example, fixed periods or can be fully or partiallydependent on detected temperatures (e.g., temperatures detected by athermocouple (not shown) of the neuromodulation assembly 110). In someembodiments, a first stage can include cooling tissue until a firsttarget temperature is reached. A second stage can include maintainingcooling for a set period, such as 15-180 seconds (e.g., 90 seconds). Athird stage can include terminating or decreasing cooling to allow thetissue to warm to a second target temperature higher than the firsttarget temperature. A fourth stage can include continuing to allow thetissue to warm for a set period, such as 10-120 seconds (e.g., 60seconds). A fifth stage can include cooling the tissue until the firsttarget temperature (or a different target temperature) is reached. Asixth stage can include maintaining cooling for a set period, such as15-180 seconds (e.g., 90 seconds). A seventh stage can, for example,include allowing the tissue to warm completely (e.g., to reach a bodytemperature).

The neuromodulation assembly 110 can then be located at a second targetsite in or near a second immune system blood vessel (e.g., a splenicartery or vein), and correct positioning of the assembly 110 can bedetermined. In selected embodiments, a contrast material can bedelivered distally beyond the neuromodulation assembly 110 andfluoroscopy and/or other suitable imaging techniques can be used tolocate the second immune system vessel. The method continues by applyingtargeted heat or cold to effectuate immune system neuromodulation at thesecond target site to cause partial or full denervation of the immunesystem organ associated with the second target site.

After providing the therapeutically-effective neuromodulation energy(e.g., cryogenic cooling, RF energy, ultrasound energy, etc.), themethod may also include determining whether the neuromodulationtherapeutically treated an immune system condition, a conditionassociated with sympathetic activity in an immune system organ, or acondition associated with central sympathetic activity or otherwisesufficiently modulated nerves or other neural structures proximate thefirst and second target sites. For example, the process of determiningwhether the neuromodulation therapeutically treated the nerves caninclude determining whether nerves were sufficiently modulated orotherwise disrupted to reduce, suppress, inhibit, block or otherwiseaffect the afferent and/or efferent immune system signals (e.g., byevaluation of suitable biomarkers, stimulation and recording of nervesignals, etc.). In a further embodiment, patient assessment could beperformed at time intervals (e.g., 1 month, 3 months, 6 months, 12months) following neuromodulation treatment. For example, the patientcan be assessed for measurements of perceived fatigue, fever, jointpain, stiffness, or swelling, skin lesions, shortness of breath, chestpain, headaches, confusion, clumsiness, tingling, or weakness, or forone or more physiological parameters selected from, for example, MSNA,norepinephrine spillover to plasma, whole body norepinephrine spillover,heart rate variability, antibody titer, or WBC count.

In other embodiments, various steps in the method can be modified,omitted, and/or additional steps may be added. In further embodiments,the method can have a delay between applying therapeutically-effectiveneuromodulation energy at a first target site at or near a first immunesystem blood vessel and applying therapeutically-effectiveneuromodulation energy at a second target site at or near a secondimmune system blood vessel. For example, neuromodulation of the firstimmune system blood vessel can take place at a first treatment session,and neuromodulation of the second immune system blood vessel can takeplace at a second treatment session at a later time.

As discussed previously, treatment procedures for modulation of immunesystem nerves in accordance with embodiments of the present technologyare expected to improve at least one condition associated with an immunesystem condition and/or with sympathetic activity in an immune systemorgan or a condition associated with central sympathetic activity. Forexample, with respect to an autoimmune condition, modulation of immunesystem nerves in accordance with embodiments of the present technologyis expected to reduce, maintain, or prevent an increase in fatigue,fever, joint pain, stiffness, or swelling, skin lesions, shortness ofbreath, chest pain, headaches, confusion, clumsiness, tingling, orweakness. With respect to central sympathetic activity (e.g.,overactivity or hyperactivity), for example, modulation of immune systemnerves is expected to reduce MSNA and/or whole body norepinephrinespillover in patients. These and other clinical effects are expected tobe detectable immediately after a treatment procedure or after a delay,e.g., of 1, 2, or 3 months. In some embodiments, it may be useful torepeat immune system neuromodulation at the same treatment location or adifferent treatment location after a suitable delay, e.g., 1, 2, or 3years. In still other embodiments, however, other suitable treatmentregimens or techniques may be used.

VII. Pertinent Anatomy and Physiology

The following discussion provides further details regarding pertinentpatient anatomy and physiology. This section is intended to supplementand expand upon the previous discussion regarding the relevant anatomyand physiology, and to provide additional context regarding thedisclosed technology and the therapeutic benefits associated with immunesystem neuromodulation.

A. The Sympathetic Nervous System

The SNS is a branch of the autonomic nervous system along with theenteric nervous system and parasympathetic nervous system. It is alwaysactive at a basal level (called sympathetic tone) and becomes moreactive during times of stress. Like other parts of the nervous system,the SNS operates through a series of interconnected neurons. Sympatheticneurons are frequently considered part of the peripheral nervous system(PNS), although many lie within the CNS. Sympathetic neurons of thespinal cord (which is part of the CNS) communicate with peripheralsympathetic neurons via a series of sympathetic ganglia. Within theganglia, spinal cord sympathetic neurons join peripheral sympatheticneurons through synapses. Spinal cord sympathetic neurons are thereforecalled presynaptic (or preganglionic) neurons, while peripheralsympathetic neurons are called postsynaptic (or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine binds adrenergic receptors on peripheraltissues. Binding to adrenergic receptors causes a neuronal and hormonalresponse. The physiologic manifestations include pupil dilation,increased heart rate, occasional vomiting, and increased blood pressure.Increased sweating is also seen due to binding of cholinergic receptorsof the sweat glands.

The SNS is responsible for up- and down-regulation of many homeostaticmechanisms in living organisms. Fibers from the SNS innervate tissues inalmost every organ system, providing at least some regulatory functionto physiological features as diverse as pupil diameter, gut motility,and urinary output. This response is also known as the sympathoadrenalresponse of the body, as the preganglionic sympathetic fibers that endin the adrenal medulla (but also all other sympathetic fibers) secreteacetylcholine, which activates the secretion of adrenaline (epinephrine)and to a lesser extent noradrenaline (norepinephrine). Therefore, thisresponse that acts primarily on the cardiovascular system is mediateddirectly via impulses transmitted through the SNS and indirectly viacatecholamines secreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the SNS operated inearly organisms to maintain survival as the SNS is responsible forpriming the body for action. One example of this priming is in themoments before waking, in which sympathetic outflow spontaneouslyincreases in preparation for action.

1. The Sympathetic Chain

As shown in FIG. 3, the SNS provides a network of nerves that allows thebrain to communicate with the body. Sympathetic nerves originate insidethe vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors that connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons travel longdistances in the body. Many axons relay their message to a second cellthrough synaptic transmission. The first cell (the presynaptic cell)sends a neurotransmitter across the synaptic cleft (the space betweenthe axon terminal of the first cell and the dendrite of the second cell)where it activates the second cell (the postsynaptic cell). The messageis then propagated to the final destination.

In the SNS and other neuronal networks of the peripheral nervous system,these synapses are located at sites called ganglia, discussed above. Thecell that sends its fiber to a ganglion is called a preganglionic cell,while the cell whose fiber leaves the ganglion is called apostganglionic cell. As mentioned previously, the preganglionic cells ofthe SNS are located between the first thoracic (T1) segment and thirdlumbar (L3) segments of the spinal cord. Postganglionic cells have theircell bodies in the ganglia and send their axons to target organs orglands. The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

FURTHER EXAMPLES

1. A method of treating a human patient diagnosed with an immune systemcondition, the method comprising:

-   -   intravascularly positioning a neuromodulation assembly within an        immune system blood vessel of the patient and adjacent to a        target immune system nerve of the patient; and    -   reducing sympathetic neural activity in the patient by        delivering energy to the immune system nerve via the        neuromodulation assembly to modulate a function of the immune        system nerve,    -   wherein reducing sympathetic neural activity improves a        measurable physiological parameter corresponding to the immune        system condition of the patient.

2. The method of example 1 wherein the immune system condition is anautoimmune condition.

3. The method of example 2 wherein the autoimmune condition is selectedfrom the group consisting of multiple sclerosis, lupus, and psoriasis.

4. The method of any one of examples 1-3 wherein reducing sympatheticneural activity in the patient in a manner that improves a measurablephysiological parameter corresponding to the immune system conditioncomprises reducing muscle sympathetic nerve activity in the patient.

5. The method of any one of examples 1-3 wherein reducing sympatheticneural activity in the patient in a manner that improves a measurablephysiological parameter corresponding to the immune system conditioncomprises reducing whole body norepinephrine spillover in the patient.

6. The method of any one of examples 1-5 wherein intravascularlypositioning a neuromodulation assembly within an immune system bloodvessel comprises positioning the neuromodulation assembly in at leastone of the splenic artery, splenic branch artery, or splenic vein.

7. The method of any one of examples 1-6 wherein reducing sympatheticneural activity in the patient by delivering energy to the immune systemnerve comprises at least partially inhibiting afferent neural activity.

8. The method of any one of examples 1-6 wherein reducing sympatheticneural activity in the patient by delivering energy to the immune systemnerve comprises at least partially inhibiting efferent neural activity.

9. The method of any one of examples 1-8 wherein reducing sympatheticneural activity in the patient by delivering energy to the immune systemnerve comprises partially ablating the target immune system nerve.

10. The method of any one of examples 1-9 wherein reducing sympatheticneural activity in the patient by delivering energy to the immune systemnerve via the neuromodulation assembly comprises delivering an energyfield to the target immune system nerve via the neuromodulationassembly.

11. The method of example 10 wherein delivering an energy field to thetarget immune system nerve comprises delivering radio frequency (RF)energy via the neuromodulation assembly.

12. The method of example 10 wherein delivering an energy field to thetarget immune system nerve comprises delivering ultrasound energy viathe neuromodulation assembly.

13. The method of example 12 wherein delivering ultrasound energycomprises delivering high intensity focused ultrasound energy via theneuromodulation assembly.

14. The method of example 10 wherein delivering an energy field to thetarget immune system nerve comprises delivering laser energy via theneuromodulation assembly.

15. The method of example 10 wherein delivering an energy field to thetarget immune system nerve comprises delivering microwave energy via theneuromodulation assembly.

16. The method of any one of examples 1-15, further comprising removingthe neuromodulation assembly from the patient after delivering energy tothe immune system nerve via the neuromodulation assembly to modulate afunction of the immune system nerve.

17. A method, comprising:

-   -   percutaneously introducing a neuromodulation assembly at a        distal portion of a treatment device proximate to neural fibers        innervating an immune system organ of a human subject diagnosed        with an immune system condition; partially disrupting function        of the neural fibers via the neuromodulation assembly;    -   and removing the neuromodulation assembly from the subject after        treatment,    -   wherein partial disruption of the function of the neural fibers        therapeutically treats one or more symptoms associated with the        immune system condition of the subject.

18. The method of example 17 wherein partially disrupting function ofthe neural fibers via the neuromodulation assembly comprises deliveringa chemical agent to tissue at a treatment location proximate the neuralfibers in a manner that modulates sympathetic neural activity of theneural fibers.

19. The method of example 17 wherein partially disrupting function ofthe neural fibers via the neuromodulation assembly comprises thermallymodulating the neural fibers via at least one wall-contact electrode.

20. The method of example 17 wherein partially disrupting function ofthe neural fibers via the neuromodulation assembly comprises thermallymodulating the neural fibers via a multi-electrode array positionedwithin an immune system blood vessel of the patient.

22. The method of example 17 wherein partially disrupting function ofthe neural fibers via the neuromodulation assembly comprisescryotherapeutically cooling the neural fibers via the neuromodulationassembly.

22. A device for carrying out the method of any of examples 1-21.

CONCLUSION

The above detailed descriptions of embodiments of the present technologyare for purposes of illustration only and are not intended to beexhaustive or to limit the present technology to the precise form(s)disclosed above. Various equivalent modifications are possible withinthe scope of the present technology, as those skilled in the relevantart will recognize. For example, while steps may be presented in a givenorder, alternative embodiments may perform steps in a different order.The various embodiments described herein and elements thereof may alsobe combined to provide further embodiments. In some cases, well-knownstructures and functions have not been shown or described in detail toavoid unnecessarily obscuring the description of embodiments of thepresent technology.

Where the context permits, singular or plural terms may also include theplural or singular term, respectively. Moreover, unless the word “or” isexpressly limited to mean only a single item exclusive from the otheritems in reference to a list of two or more items, then the use of “or”in such a list is to be interpreted as including (a) any single item inthe list, (b) all of the items in the list, or (c) any combination ofthe items in the list. Additionally, the terms “comprising” and the likeare used throughout the disclosure to mean including at least therecited feature(s) such that any greater number of the same feature(s)and/or additional types of other features are not precluded. It willalso be appreciated that various modifications may be made to thedescribed embodiments without deviating from the present technology.Further, while advantages associated with certain embodiments of thepresent technology have been described in the context of thoseembodiments, other embodiments may also exhibit such advantages, and notall embodiments need necessarily exhibit such advantages to fall withinthe scope of the present technology. Accordingly, the disclosure andassociated technology can encompass other embodiments not expresslyshown or described herein.

1-20. (canceled)
 21. A neuromodulation apparatus for treating a humanpatient diagnosed with an immune system condition, the neuromodulationapparatus comprising: an energy delivery console external to thepatient; and a catheter including an energy delivery element sized andshaped for intravascular placement within a blood vessel proximate totarget neural fibers innervating an immune system organ of the patient,wherein the energy delivery element is operably coupled to the energydelivery console, wherein the energy delivery console causes delivery ofan energy field, via the energy delivery element, to the target neuralfibers innervating the immune system organ of the patient, and whereindelivery of the energy field at least partially disrupts communicationalong the target neural fibers innervating the immune system organ andimproves a measurable physiological parameter corresponding to theimmune system condition of the patient.
 22. The neuromodulationapparatus of claim 21 wherein a distal portion of the catheter furthercomprises an expandable element configured for expansion from alow-profile delivery configuration to an expanded deployed configurationwithin the blood vessel of the patient.
 23. The neuromodulationapparatus of claim 22 wherein the expandable element is configured tocenter the energy delivery element within the blood vessel of thepatient.
 24. The neuromodulation apparatus of claim 22 wherein theexpandable element is configured to position the energy delivery elementin contact with an inner wall of the blood vessel of the patient. 25.The neuromodulation apparatus of claim 22 wherein the expandable elementcomprises an inflatable balloon.
 26. The neuromodulation apparatus ofclaim 25 wherein the inflatable balloon comprises the energy deliveryelectrode.
 27. The neuromodulation apparatus of claim 21 wherein theenergy delivery element is configured to deliver radio frequency (RF)energy to the target neural fibers.
 28. The neuromodulation apparatus ofclaim 27 wherein the energy delivery console is configured to deliversufficient RF energy to ablate the target neural fibers innervating theimmune system organ of the patient.
 29. The neuromodulation apparatus ofclaim 27 wherein the energy delivery console is configured to deliversufficient RF energy to partially ablate the target neural fibersinnervating the immune system organ of the patient,.
 30. Theneuromodulation apparatus of claim 21 wherein the energy deliveryconsole is configured to deliver ultrasound energy, via the energydelivery element, to the target neural fibers innervating the immunesystem organ of the patient.
 31. The neuromodulation apparatus of claim21 wherein the energy delivery console is configured to deliver highintensity focused ultrasound energy, via the energy delivery element, tothe target neural fibers innervating the immune system organ of thepatient.
 32. The neuromodulation apparatus of claim 21 wherein theenergy delivery console is configured to deliver laser energy, via theenergy delivery element, to the target neural fibers innervating theimmune system organ of the patient.
 33. The neuromodulation apparatus ofclaim 21 wherein the energy delivery console is configured to delivermicrowave energy, via the energy delivery element, to the target neuralfibers innervating the immune system organ of the patient.
 34. Theneuromodulation apparatus of claim 21 wherein the energy deliveryconsole is configured to deliver cytotherapeutic energy, via the energydelivery element, to the target neural fibers innervating the immunesystem organ of the patient.
 35. The neuromodulation apparatus of claim21 wherein the catheter is configured for intravascular placement withinthe blood vessel innervating the immune system organ of the patient overa guidewire.
 36. The neuromodulation apparatus of claim 21 wherein thecatheter including the energy delivery element is sized and shaped forintravascular placement within at least one of the splenic artery,splenic branch artery, or splenic vein of the patient.
 37. Theneuromodulation apparatus of claim 21 wherein the catheter furthercomprises an element for monitoring at least one physiological parameterof the patient.
 38. The neuromodulation apparatus of claim 21 wherein atleast partially disrupting communication along the target neural fibersinnervating the immune system organ via delivery of the energy fieldcomprises reducing a degree of inflammation in the subject.
 39. Theneuromodulation apparatus of claim 21 wherein at least partiallydisrupting communication along the target neural fibers innervating theimmune system organ via delivery of the energy field comprises reducinga level of one or more markers of inflammation in the patient.
 40. Theneuromodulation apparatus of claim 39 wherein at least one of themarkers of inflammation is selected from the group consisting ofinterleukins, high-sensitivity C-reactive proteins, erythrocytesedimentation rate, and heat shock proteins.
 41. The neuromodulationapparatus of claim 21 wherein at least partially disruptingcommunication along the target neural fibers innervating the immunesystem organ via delivery of the energy field comprises improving anantibody titer or a white blood cell count in the patient within aboutthree months to about 12 months after at least partially disruptingcommunication along the target neural fibers via delivery of the energyfield.